Abstract

Purpose

The association of recreational physical activity (RPA) with mortality is well established only for breast and colon cancers and few studies have evaluated relationships for exercising before and after diagnosis, across multiple disease sites. We examined the joint associations of pre- and post- diagnosis RPA with mortality in a cohort of 5,807 patients enrolled in the Data Bank and BioRepository at Roswell Park.

Methods

Patients were classified into one of four activity categories (habitually active, increased activity after diagnosis, decreased activity after diagnosis, habitually inactive). Cox proportional hazards models were used to estimate the associations of activity status with mortality.

Conclusion

Low-to-moderate frequency pre- and post-diagnosis RPA was associated with significantly decreased mortality in patients diagnosed with a variety of malignancies. These observations solidify the clinical and public health importance of the message that some regular activity is better than inactivity, which is particularly encouraging, given that cancer survivors can be overwhelmed by current daily physical activity recommendations.

Keywords

Physical activity Survival Mortality

Abbreviations

RPA

Recreational physical activity

MVPA

Moderate-to-vigorous intensity physical activity

BMI

Body mass index

DBBR

Data Bank and BioRepository

Electronic supplementary material

Introduction

As the number of cancer survivors in the US increases, their physical activity patterns are becoming an important focus of scientific inquiry, because maintenance or adoption of an active lifestyle has the potential to reduce morbidity and mortality and dramatically improve quality of life among this population [1]. Yet, inverse associations between pre- and post-diagnosis recreational physical activity (RPA) with mortality have only been well established for breast and colorectal cancer [2, 3], with mounting evidence for prostate cancer.

To date, surprisingly few reports have described the associations of RPA with cancer outcomes across multiple disease sites among men and women in the United States [4, 5, 6, 7, 8, 9, 10, 11]. Furthermore, few studies have examined the associations for both pre- and post-diagnosis RPA, and little is known about how changes in RPA relative to cancer diagnosis may be associated with survival. Given the growing burden of cancer in the aging population and the prevalence of physical inactivity among cancer patients and survivors, we sought to examine the associations of pre- and post- diagnosis RPA with mortality in a large cohort of men and women diagnosed with primary incident cancer at Roswell Park Comprehensive Cancer Center.

Methods

Study population

We conducted the current analyses using patient data from the Roswell Park Data Bank and BioRepository (DBBR), an NCI cancer center support grant shared resource. Established in 2003, the DBBR obtains informed consent from newly diagnosed adult patients for the completion of an extensive epidemiological questionnaire, collection of a blood specimen, and permission to link epidemiological and bio-specimen data to additional clinical data. Herein, we included 5,807 participants diagnosed with a malignant tumor who enrolled in the DBBR between 2003 and 2016, and who completed their epidemiological questionnaire within 1 year after diagnosis (median time between diagnosis and questionnaire completion was 53 days). The protocols for the DBBR and the current analyses were approved by the Roswell Park Institutional Review Board, and all DBBR participants provided informed consent.

Epidemiological questionnaire

The DBBR questionnaire is an extensive, self-administered epidemiological survey designed to ascertain patient demographic and lifestyle factors, including RPA. The questionnaire includes a detailed assessment of medical history and RPA prior to enrollment (i.e., frequency, intensity, duration, and mode of RPA performed in the decade prior to study enrollment) as well as a brief assessment of “Current Lifestyle” and RPA at the time of questionnaire completion. Upon submission of the DBBR questionnaire, each completed survey is reviewed by a data manager and a dedicated research associate who re-contacts patients via telephone to clarify any data discrepancies prior to scanning data for storage. During the time of enrollment for the current study (1 January 2003 through 31 December 2016), 77.68% of all patients approached consented to enrollment in the DBBR.

Recreational physical activity

In the current analysis, we examined moderate-to-vigorous intensity aerobic recreational physical activities in association with cancer outcomes. Three activity exposures of interest were examined, including RPA in the decade prior to DBBR enrollment (i.e., pre-diagnosis RPA), RPA within 1 year after diagnosis (i.e., post-diagnosis RPA), and a derived joint-exposure variable (i.e., habitual RPA), our primary analytic exposure of interest.

Pre-diagnosis RPA

DBBR questionnaire items pertaining to pre-diagnosis RPA assessed frequency of exercise (days/week), duration of exercise (minutes/session), length of time exercising (years), and mode of exercise, including walking for exercise or other moderate or vigorous intensity physical activities (MVPA) such as “running, aerobics, swimming, or cycling.”

Post-diagnosis RPA

Post-diagnosis RPA was queried in the “Current Lifestyle” section of the DBBR questionnaire; these data were less detailed than those provided for pre-diagnostic RPA. Respondents indicated how many days/week they performed at least 20 minutes/session of MVPA. Because all respondents included in the current analysis completed their questionnaire within 1 year after diagnosis, these data reflect post-diagnosis RPA.

Habitual RPA

Information on days/week (frequency) of performing MVPA was available for both pre- and post-diagnosis RPA, thus, habitual RPA was developed as a joint-exposure variable from self-reported frequency of pre- and post-diagnosis RPA. To derive this variable, patients were first categorized as engaging in regular, weekly, pre- or post-diagnosis RPA (inactive/active). “Regular” pre-diagnosis RPA was defined as a minimum of 1–2 sessions per/week for a minimum of 1–3 years; regular post-diagnosis RPA was defined as a minimum of 1–2 sessions per/week. Next, patients were categorized into one of four joint-exposure groups: inactive pre- and post-diagnosis (habitually inactive), inactive pre- and active post-diagnosis (increased activity), active pre- and inactive post-diagnosis (decreased activity), or active pre- and post-diagnosis (habitually active).

Clinical outcomes

We examined associations of RPA exposures with all-cause and cancer-specific mortality. For all-cause mortality, survival time was calculated from the date of diagnosis until the date of death from any cause; patients not deceased were censored at the date of last clinical contact. For cancer mortality, survival time was measured from the date of diagnosis until the date of death from cancer or complications from cancer. Patients with death from non-cancer causes were censored at the date of death from other causes or date of last clinical contact. Vital status was obtained from Roswell Park Cancer Registry, with updates obtained in January 2018. Because death certificate verification is only conducted for patients dying at Roswell, all-cause mortality is the primary outcome of interest.

Statistical analyses

We used Cox-proportional hazards models to estimate the associations of pre-diagnosis, post-diagnosis, and habitual RPA with mortality. For all multivariable analyses, we a priori defined age at diagnosis, sex, tumor stage, and smoking status as important covariates. We examined additional epidemiological and clinical variables for confounding using the 10% change-in-estimate method [12]. Additional variables tested included Body Mass Index (BMI), race, education, alcohol consumption, tumor grade, type of treatment completed (surgery only, adjuvant only, adjuvant plus post-adjuvant, neoadjuvant plus adjuvant, unknown), occupational activity, and comorbidities (i.e., diabetes, asthma, emphysema, COPD, rheumatoid arthritis, and osteoarthritis). For female participants, we also assessed the potential confounding role of reproductive variables such as menopausal status and hormone replacement use. Importantly, treatment regimen, BMI, and education did not meet the definition of a confounder according to our a priori criteria, and were not included in final multivariable models. Furthermore, although detailed exercise duration, intensity, and mode information was not available for post-diagnosis RPA, associations for frequencies, durations, minutes, and intensity of pre-diagnosis RPA were investigated in exploratory analyses.

In a series of sub-group analyses according to varying clinical and epidemiological characteristics among patients, we examined the association of habitual RPA with mortality according to strata by disease site, tumor stage, treatment type, BMI, smoking status, sex, and age of diagnosis. For BMI analyses, we excluded underweight patients due to a strong correlation with cancer cachexia and mortality, and because we were primarily interested in examining whether associations of RPA with mortality were independent of overweight and/or obesity. For all sub-group analyses aside from disease site, if we observed evidence that HRs varied considerably across strata, we evaluated the potential for statistical interaction via the inclusion of a cross-product term in multivariable models and declared significance at p < 0.01.

To estimate the associations of habitual RPA with mortality while accounting for statistical heterogeneity by disease site, we applied the DerSimonian and Laird random-effects meta-analytic technique [13]. Disease sites with less than 30 events were excluded from the meta-analysis and heterogeneity by disease site was evaluated by the Cochran Q-statistic (p < 0.05) and I2 statistic (> 50%) [14].

In sensitivity analyses, to minimize the chance that our observed results were due to a healthy survivor bias, we excluded patients with < 3 years of follow-up. We further excluded patients diagnosed with breast, colorectal, and prostate cancer to examine whether the association between RPA and mortality could be observed among less common tumors for which a well-established inverse association between physical activity and mortality has not been apparent in the scientific literature. Lastly, we conducted additional sensitivity analyses designed to examine potential biases associated with the variability in length of time between the date of diagnosis and the date of questionnaire completion. To accomplish this, we stratified analyses according to sub-groups of patients who completed questionnaires within 6, 12, 18, 24, and 30 months of diagnosis.

Proportional hazards assumptions were tested for all RPA exposure variables and covariates via visual inspection of log–log plots and by assessing a time*covariate cross-product interaction term for statistical significance (p < 0.01) in multivariable models. Statistical analyses were performed using IBM SPSS Statistics 21.0, and were independently confirmed by a second data analyst. Meta-analysis was conducted utilizing Comprehensive Meta-analysis Software. All statistical tests were two-tailed and considered statistically significant at p < 0.05 unless otherwise noted.

Forest plots of the hazard ratios and 95% confidence intervals representing the associations of habitual recreational physical activity, in comparison to habitual inactivity, with all-cause mortality (a) and cancer-specific mortality (b) by disease site. Multivariable models were adjusted for age of diagnosis, sex, tumor stage, and smoking. The random-effects summary estimates are presented in both figures because significant heterogeneity was noted. Each square represents the disease site-specific HRs and the corresponding horizontal lines represent the width of the 95% CIs. The weighted, summary HR and its 95% CI is represented by the diamond in each figure

In additional sub-group analyses by clinical characteristics such as tumor stage, we observed significant inverse associations between habitual activity and mortality among patients diagnosed with Stage I, II, III, and IV disease (Table 5). However, the association was somewhat attenuated among patients with Stage IV disease; among patients with unknown staging and/or among patients in which staging was not applicable (i.e., hematological cancer), the association between habitual activity and mortality was not significant (p for-interaction = 0.051 for all-cause and 0.227 for cancer-specific mortality, Table 5).

We further examined the associations between habitual RPA and mortality according to treatment regimen (Supplemental Table 2). We observed inverse associations between habitual activity and mortality across all treatment types, but the association was not significant among patients receiving neoadjuvant treatment. In these analyses, we observed some evidence of a treatment*activity interaction for all-cause mortality (p for-interaction < 0.001), but not for cancer-specific mortality (p for-interaction = 0.036). Additional evaluation of the associations of habitual RPA with mortality stratified by epidemiological characteristics including age, sex, smoking status, and BMI classification did not support effect modification by any of these factors (Supplemental Table 3).

Discussion

In our study of the Roswell Park DBBR cancer patient cohort, we made four principle observations that expand the current knowledge regarding the associations of pre- and post-diagnosis RPA with mortality, each having important implications in the context of cancer survivorship. First, in comparison to patients who were habitually inactive, we observed a marked survival advantage among patients who reported regular RPA before and after diagnosis in the overall study population and in eight disease sites including breast, colon, prostate, ovarian, bladder, endometrial, esophageal, and skin cancer. Previous reports depicting the associations of pre- and post-diagnosis RPA with cancer mortality are sparse, [2, 15, 16, 17, 18, 19, 20, 21, 22], and to our knowledge, none have examined associations with cancer mortality across multiple disease sites. We observed the expected associations for breast and colon cancer [2] and our findings of an inverse association for prostate cancer are consistent with one previous report demonstrating that men who were active before and after diagnosis experienced the lowest risk of mortality [16]. Our findings are congruent with previous reports showing that pre- or post- diagnosis RPA was associated with ovarian [23, 24, 25, 26], bladder [27], and esophageal cancer mortality [28]. Lastly, our observation that RPA is inversely associated with endometrial cancer mortality coincides with one previous report [29] and conflicts with another that found no association [30]. Collectively, these data extend our current knowledge base by providing evidence that RPA is associated with improved outcomes among patients diagnosed with a variety of less common tumors.

Second, one of the most striking observations in the present study was that previously inactive patients in the decade prior to diagnosis, who reported engaging in regular, weekly RPA after diagnosis experienced a significantly reduced hazard of mortality in comparison to patients who remained inactive. These findings have important implications in the oncology setting because they suggest that a cancer diagnosis serves as an impetus for healthy behavior change in some patients, and among these patients, beginning an exercise program after diagnosis resulted in a significant survival advantage.

A third principle finding was that patients reporting 3–4 days/week of pre or post-diagnosis RPA experienced the best survival, while patients reporting 1–2 days of regular, weekly, pre-, and post-diagnosis RPA experienced similar survival to patients reporting 5–7 days per/week. These findings extend our knowledge about the benefits of low-frequency RPA and are consistent with two recently published reports demonstrating that 1–2 days/week of RPA was associated with a 17–21% reduced hazard of cancer-specific mortality in comparison to inactive participants [10] and that even the smallest amounts of daily physical activity associated with decreased all-cause mortality in post-menopausal women [31]. These data are also somewhat consistent with previously published meta-analyses showing that the association of RPA with mortality is non-linear [2, 32, 33]. To this end, it has been consistently reported in the exercise science literature that the association between physical activity and health benefits is curvilinear [34], with the steepest curve (i.e., the most significant health or survival benefits) occurring at the lower ends of the activity continuum and benefits plateauing [34] or decreasing [35, 36] at higher ends of the activity continuum. Collectively, these observations solidify the clinical and public health importance of the message that any amount of regular, weekly activity is better than inactivity, which is particularly encouraging given that cancer patients and survivors can be overwhelmed by the current physical activity recommendations of 30 min per day of moderate-intensity physical activity.

Fourth, we examined the association between habitual RPA and mortality in sub-groups according to tumor stage, BMI classification, smoking status, sex, and age, and found no support for effect modification by any of these factors. In fact, the significant inverse association between habitual RPA and mortality was consistently observed across all tumor stages, all smoking status categories, and among normal weight and overweight/obese patients, demonstrating that habitual RPA is an independent, modifiable predictor of mortality, even among patients diagnosed with advanced disease and among patients who were obese and persistent smokers.

In sub-group analyses stratified by treatment regimen, we observed some evidence that the association between habitual activity and mortality was attenuated as treatment regimens intensified. For example, among patients receiving neoadjuvant therapy, the association between habitual activity and mortality was not significant. However, upon further examination of these data, we noted that the neoadjuvant treatment group comprised mostly of patients diagnosed with hematological and lung malignancies for which we observed no associations in sub-group analyses by disease site. Furthermore, patients undergoing neoadjuvant therapy also experienced the greatest percentage of events and were more likely to become inactive after diagnosis (29% vs. 22% for patients undergoing other treatment regimens). To this end, we acknowledge that the patients who stopped exercising after diagnosis were possibly the sickest patients and/or were undergoing the most difficult treatments, and sub-group analyses by treatment regimen support this assertion. However, we also observed a significant inverse association between habitual activity and mortality among patients diagnosed with stage IV disease, which may argue against a reverse-causation bias. Importantly, our method of comparing mortality in patients who were active as a lifestyle, in reference to those who were inactive as a lifestyle, potentially reduced the impact of a reverse-causation bias that might be observed if the sickest patients were active before diagnosis but stopped exercising after diagnosis.

The most commonly cited mechanisms explaining the associations between RPA and cancer mortality include a decrease in circulating levels of sex hormones, decreased chronic inflammation, improved insulin sensitivity, improved immune surveillance, improved adipokine milieu (i.e., decreased leptin and increased adiponectin), and decreased adiposity [37, 38]. While it has long been hypothesized that physical activity reduces cancer risk and decreases cancer mortality primarily by lowering body weight [5, 37, 38], there has been an increasing recognition that RPA may be associated with cancer endpoints through pathways that are, at least, in part, independent from obesity-related pathways [39, 40, 41].

In our analyses, the association of habitual RPA with mortality was not confounded by BMI, nor did we observe evidence of effect modification across sub-groups of BMI, suggesting that the observed association of habitual RPA with mortality is independent of obesity. Furthermore, emerging data from animal models suggest that voluntary aerobic exercise in tumor-bearing mice enhances sensitivity to chemotherapy by way of decreasing hypoxia and directly suppresses tumor growth and progression by enhancing the immune response to transformed cells, which is subsequently accompanied by more than a 60% reduction in tumor growth across several mouse models [42, 43]. Additional mechanistic studies have demonstrated that myokines secreted by contracting skeletal muscle, such as secreted protein acidic and rich cysteine (SPARC) and calprotectin, likely prevent carcinogenesis through the promotion of autophagy, apoptosis, and anti-tumor immunity, while preventing invasion and metastases [41].

The primary strength of our study was the availability of epidemiological data for 5,807 participants, including detailed clinical follow-up data spanning 14 years, and RPA data encompassing pre- and post-diagnosis exposure windows. That is, reliance solely upon pre-diagnosis RPA does not account for changes in activity throughout follow-up and reliance upon post-diagnosis RPA cannot rule out reverse-causation bias. We contend that deriving a joint pre- and post-diagnosis RPA exposure and identifying habitual RPA as the primary exposure of interest potentially reduced the impact of these biases by identifying and comparing patients who were (in)active as a lifestyle.

A primary limitation of our study remains the reliance upon self-reported RPA data, which may be subject to recall error and misclassification and this can be especially true for the exposure window spanning the decade prior to diagnosis. Furthermore, unlike the pre-diagnosis DBBR RPA questionnaire items, the post-diagnosis RPA survey items did not yield detailed information about the mode, intensity, or specific duration of RPA. Thus, the habitual physical activity variable is based primarily upon weekly frequency of RPA. Despite this limitation, the DBBR questionnaire yielded the expected prevalence of pre- and post-diagnosis physical inactivity, and we observed the anticipated associations between activity and mortality for breast and colorectal cancer [2]. In fact, the inactivity prevalence data reported herein are nearly identical to recently reported national statistics suggesting that between 24.0 and 25.4% of the general population are inactive [44] and between 38.3 and 42.0% of adult cancer patients are inactive [1], thus bolstering our confidence in the generalizability and validity of these data.

An additional limitation of the current analysis was a lack of continued follow-up of RPA collected across multiple time points after study enrollment. As such, if post-diagnostic RPA levels changed after questionnaire completion and throughout the follow-up period, our observed estimates could be biased. Further, although we assessed the role of several potential confounders, we cannot entirely rule out the possibility that residual confounding by measured or unmeasured factors influenced our results. We also cannot rule out the possibility that our findings are due to a healthy survivor effect. We attempted to minimize the possibility of a healthy survivor bias by conducting sensitivity analyses to exclude participants who died within 3 years of diagnosis and the point estimates in our primary analyses were strengthened.

Additional limitations include a lack of detailed treatment data and the reliance upon Roswell Park Cancer Registry data for cause-specific death; verification by death certificate was only available for patients dying at Roswell Park. We also acknowledge that the heterogeneity of the DBBR patient cohort is a limitation of the current analysis. Yet, from a public health and survivorship standpoint, it is imperative to demonstrate that the inverse association between physical activity and mortality was observed among patients diagnosed with a variety of malignancies. Lastly, despite the overall size of the DBBR patient cohort, we lacked sufficient statistical power to conduct meaningful multivariable and sub-group analyses for more rare disease sites for which more research is needed regarding the associations of RPA with clinical outcomes.

Conclusion

Regular participation in RPA before and after a cancer diagnosis was associated with decreased mortality in the overall study population and in patients diagnosed with 8 specific tumors. Importantly, the current study suggests that beginning a regular RPA program after a cancer diagnosis yields a significant survival advantage in comparison to patients who remained inactive, and that as little as 1–2 days per/week of regular, weekly RPA associated with significant reductions in mortality. These data demonstrate the potential value of implementing exercise into the supportive care continuum of cancer patients and can inform targeted intervention trials designed to improve clinical outcomes among patients diagnosed with a variety of malignancies.

Notes

Funding

The study was funded in part by the Roswell Park Cancer Center Support Grant Shared Resource, supported by the National Cancer Institute Grant P30CA016056; Arinden Sen is supported by NIH R21CA194634 (AS).

Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest.

Ethical approval

The research described herein was approved by Roswell Park’s IRB. Thus, all procedures and analyses performed were in accordance with the ethical standards of Roswell Park and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all participants included in the DBBR study.